Targeting XPO1 and PAK4 in 8505C Anaplastic Thyroid Cancer Cells: Putative Implications for Overcoming Lenvatinib Therapy Resistance

International Journal of Molecular Sciences

Irfana Muqbil¹  Misako Nagasaka²  RamziM. Mohammad²  Mark Szlaczky²  Mahmoud Chaker²  James Ge²  Gabriel Mpilla²  HusainYar Khan²  Ammar Sukari²  Amro Aboukameel²  AsfarS. Azmi²  Yosef Landesman³  Erkan Baloglu⁴ 

[1] Department of Chemistry and Biochemistry, University of Detroit Mercy, Detroit, MI 48221, USA;Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA;Karyopharm Therapeutics Inc., Newton, MA 02459, USA;Restorbio Inc., Boston, MA 02116, USA;

关键词: thyroid cancer;    lenvatinib;    therapy resistance;    selinexor;    pak4 inhibitor;    selective inhibitors of nuclear export;   

DOI  :  10.3390/ijms21010237

来源: DOAJ

【 摘 要 】

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) that shows improved median progression-free survival (PFS) in patients with thyroid carcinomas. However, virtually all patients ultimately progress, indicating the need for a better understanding of the mechanisms of resistance. Here, we examined the molecular profile of anaplastic thyroid cancer cells (8505C) exposed to lenvatinib and found that long-term exposure to lenvatinib caused phenotypic changes. Consistent with change toward mesenchymal morphology, activation of pro-survival signaling, nuclear exporter protein exportin 1 (XPO1) and Rho GTPase effector p21 activated kinases (PAK) was also observed. RNA-seq analysis showed that prolonged lenvatinib treatment caused alterations in numerous cellular pathways and several oncogenes such as CEACAM (carcinoembryonic antigen-related cell adhesion molecule) and NUPR1 (Nuclear protein 1) were also upregulated. Further, we evaluated the impact of XPO1 and PAK4 inhibition in the presence or absence of lenvatinib. Targeted inhibition of XPO1 and PAK4 could sensitize the 8505C cells to lenvatinib. Both XPO1 and PAK4 inhibitors, when combined with lenvatinib, showed superior anti-tumor activity in 8505C sub-cutaneous xenograft. These studies bring forward novel drug combinations to complement lenvatinib for treating anaplastic thyroid cancer. Such combinations may possibly reduce the chances of lenvatinib resistance in thyroid cancer patients.

【 授权许可】

Unknown